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    Clinical Trial Results:
    A Phase 3 Evaluation of BMS-790052 in Combination With Peg-Interferon Alfa-2a and Ribavirin in Treatment Naive Subjects With Chronic Hepatitis C Genotype 4

    Summary
    EudraCT number
    		 2011-002793-23
    Trial protocol
    		 GB   ES   IT   GR  
    Global end of trial date
    23 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    01 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AI444-042
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01448044
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, clinical.trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare rates of sustained virologic response at post-treatment Week 12 (SVR12) for hepatitis c virus (HCV) genotype 4 (GT-4) infected subjects treated with either BMS-790052 (daclatasvir) or placebo in combination with peginterferon-alfa plus ribavirin (pegIFNalfa/RBV).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Dec 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    France: 80
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    United States: 15
    Country: Number of subjects enrolled
    Puerto Rico: 2
    Worldwide total number of subjects
    152
    EEA total number of subjects
    135
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    148
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 26 sites in 6 countries.

    Pre-assignment
    Screening details
    		 A total of 152 subjects were enrolled in the study, of which 125 were randomized and 27 subjects were not randomized due to 23 no longer met criteria, 1 withdrew consent, 1 due to administrative reason, and 2 other reasons. Of 125 randomized, 124 were treated and 1 was not treated due to withdrawal of consent.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daclatasvir+ PegIFNα-2a + Ribavirin
    Arm description
    		 Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    BMS-790052
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daclatasvir 60 mg tablets was administered orally once daily for 24 weeks.

    Investigational medicinal product name
    Pegylated-interferon alfa 2a
    Investigational medicinal product code
    Other name
    Pegasys
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.

    Arm title
    		 Placebo + PegIFNα-2a + Ribavirin
    Arm description
    		 Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching BMS-790052 tablets was administered orally once daily for 48 weeks.

    Investigational medicinal product name
    Pegylated-interferon alfa 2a
    Investigational medicinal product code
    Other name
    Pegasys
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 48 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.

    Number of subjects in period 1 [1]
    		Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Started
    82
    42
    Completed
    59
    26
    Not completed
    23
    16
         Others
    2
    -
         Adverse event
    4
    3
         Completed 24 weeks treatment period only
    8
    -
         Subjects no longer meets study criteria
    1
    -
         Subject requested discontinue study drug
    1
    -
         Lost to follow-up
    2
    1
         Lack of efficacy
    5
    12
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 125 subjects were randomized and 124 subjects received treatment during the study.
    Period 2
    Period 2 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daclatasvir+ PegIFNα-2a + Ribavirin
    Arm description
    		 Subjects were followed up till 72 weeks. During treatment period Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    BMS-790052
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daclatasvir 60 mg tablets was administered orally once daily for 24 weeks.

    Investigational medicinal product name
    Pegylated-interferon alfa 2a
    Investigational medicinal product code
    Other name
    Pegasys
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.

    Arm title
    		 Placebo + PegIFNα-2a + Ribavirin
    Arm description
    		 Subjects were followed up till 72 weeks. During treatment period Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching BMS-790052 tablets was administered orally once daily for 48 weeks.

    Investigational medicinal product name
    Pegylated-interferon alfa 2a
    Investigational medicinal product code
    Other name
    Pegasys
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 48 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.

    Number of subjects in period 2
    		Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Started
    59
    26
    Completed
    65
    26
    Not completed
    12
    14
         Consent withdrawn by subject
    1
    1
         Other reasons
    5
    11
         Lost to follow-up
    6
    2
    Joined
    18
    14
         Subjects rejoined in Follow-up period
    18
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daclatasvir+ PegIFNα-2a + Ribavirin
    Reporting group description
    		 Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.

    Reporting group title
    Placebo + PegIFNα-2a + Ribavirin
    Reporting group description
    		 Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.

    Reporting group values
    		 Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin Total
    Number of subjects
    		 82 42 124
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 79 42 121
        From 65 to 84 years
    		 3 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.7 ± 10.23 48.4 ± 8.09 -
    Gender categorical
    Units: Subjects
        Female
    		 21 13 34
        Male
    		 61 29 90

    End points

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    End points reporting groups
    Reporting group title
    Daclatasvir+ PegIFNα-2a + Ribavirin
    Reporting group description
    		 Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.

    Reporting group title
    Placebo + PegIFNα-2a + Ribavirin
    Reporting group description
    		 Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.
    Reporting group title
    Daclatasvir+ PegIFNα-2a + Ribavirin
    Reporting group description
    		 Subjects were followed up till 72 weeks. During treatment period Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.

    Reporting group title
    Placebo + PegIFNα-2a + Ribavirin
    Reporting group description
    		 Subjects were followed up till 72 weeks. During treatment period Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.

    Primary: Percentage of Subjects With 12 Week Sustained Virologic Response (SVR12)

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    End point title
    		 Percentage of Subjects With 12 Week Sustained Virologic Response (SVR12)
    End point description
    Subjects were assessed for sustained virologic response 12 weeks post treatment (SVR12) defined as hepatitis C virus (HCV) RNA levels <lower limit of quantitation (LLOQ was 25 IU/mL), target detected (TD) or target not detected (TND) at post-treatment Week 12. The analysis was performed in modified Intent to treat population (ITT), defined as the proportions of subjects meeting the response criteria in numerator and denominator based on all treated subjects. Missing values were imputed using backward imputation technique.
    End point type
    Primary
    End point timeframe
    Week 12 (Follow-up period)
    End point values
    		 Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Number of subjects analysed
    82
    42
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Backward Imputation
    81.7 (73.3 to 90.1)
    42.9 (27.9 to 57.8)
    Statistical analysis title
    		 Percentage difference of treatments in SVR12
    Comparison groups
    Daclatasvir+ PegIFNα-2a + Ribavirin v Placebo + PegIFNα-2a + Ribavirin
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    38.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21.703
         upper limit
    		 55.997
    Notes
    [1] - The p-value is based on the Cochran-Mantel-Haenszel (CMH) test, stratified by IL28B host genotype, geography, and baseline cirrhosis status.

    Secondary: Percentage of Subjects Who Achieved HCV Ribonucleic Acid (RNA) < Limit of Quantification (LLOQ)

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    End point title
    		 Percentage of Subjects Who Achieved HCV Ribonucleic Acid (RNA) < Limit of Quantification (LLOQ)
    End point description
    Subjects who achieved HCV RNA levels below LLOQ ie, 25 international unit per milliliter (IU/mL). Subjects in the placebo arm did not have visits beyond post treatment Week 24. The analysis was performed in modified ITT population. Here ’99999’represents not estimable data for specified category in respective treatment arm.
    End point type
    Secondary
    End point timeframe
    Treatment Weeks 1, 2, 4, 6, 8 and 12; Weeks 4 and 12; End of treatment (EOT); Post treatment Week 24; Post treatment Week 48
    End point values
    		 Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Number of subjects analysed
    82
    42 [2]
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 1
    53.7 (42.9 to 64.5)
    4.8 (0 to 11.2)
        Week 2
    89 (82.3 to 95.8)
    11.9 (2.1 to 21.7)
        Week 4
    91.5 (85.4 to 97.5)
    19 (7.2 to 30.9)
        Week 6
    84.1 (76.2 to 92.1)
    40.5 (25.6 to 55.3)
        Week 8
    87.8 (80.7 to 94.9)
    47.6 (32.5 to 62.7)
        Week 12
    85.4 (77.7 to 93)
    59.5 (44.7 to 74.4)
        Weeks 4 and 12
    84.1 (76.2 to 92.1)
    19 (7.2 to 30.9)
        EOT
    92.7 (87 to 98.3)
    64.3 (49.8 to 78.8)
        Post treatment Week 24
    80.5 (71.9 to 89.1)
    40.5 (25.6 to 55.3)
        Post treatment Week 48
    83.6 (73.9 to 93.4)
    99999 (99999 to 99999)
    Notes
    [2] - As there was no visit at post treatment Week 48, SVR is depicted as 0%.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Undetectable Hepatitis C Virus (HCV) RNA Levels

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    End point title
    		 Percentage of Subjects With Undetectable Hepatitis C Virus (HCV) RNA Levels
    End point description
    Subjects who achieved HCV RNA undetectable ie, 10 international unit per milliliter (IU/mL). Subjects in the placebo arm did not have visits beyond post treatment Week 24. The analysis was performed in modified ITT population. Here ’99999’ represents not estimable data for specified category in respective treatment arm.
    End point type
    Secondary
    End point timeframe
    Treatment Weeks 1, 2, 4, 6, 8 and 12; Weeks 4 and 12, End of treatment (EOT), Post treatment Week 24, Post treatment Week 48
    End point values
    		 Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Number of subjects analysed
    82
    42 [3]
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 1
    14.6 (7 to 22.3)
    0 (0 to 0)
        Week 2
    45.1 (34.4 to 55.9)
    9.5 (0.6 to 18.4)
        Week 4
    85.4 (77.7 to 93)
    11.9 (2.1 to 21.7)
        Week 6
    80.5 (71.9 to 89.1)
    16.7 (5.4 to 27.9)
        Week 8
    87.8 (80.7 to 94.9)
    38.1 (23.4 to 52.8)
        Week 12
    84.1 (76.2 to 92.1)
    47.6 (32.5 to 62.7)
        Weeks 4 and 12 (VR 4& 12)
    79.3 (70.5 to 88)
    11.9 (2.1 to 21.7)
        EOT
    90.2 (83.8 to 96.7)
    64.3 (49.8 to 78.8)
        Post treatment Week 24
    78 (69.1 to 87)
    40.5 (25.6 to 55.3)
        Post treatment Week 48
    81.8 (71.6 to 92)
    99999 (99999 to 99999)
    Notes
    [3] - As there was no visit at post treatment Week 48, SVR is depicted as 0%.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died

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    End point title
    		 Number of Subjects With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs) and Who Died
    End point description
    AE was defined as any new unfavorable symptom, sign, or disease or worsening of a pre-existing condition that does not necessarily have a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalisation. Analysis was performed on all treated subjects.
    End point type
    Secondary
    End point timeframe
    From Day 1 (start of study treatment) up to Follow-up Week 4
    End point values
    		 Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Number of subjects analysed
    82
    42
    Units: Subjects
        AEs leading to discontinuation of study drug
    4
    3
        SAEs
    8
    2
        Death
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) or Sustained Virologic Response at Follow-up Week 24 (SVR24) by rs12979860 Single Nucleotide Polymorphism (SNP) in the IL28B Gene

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) or Sustained Virologic Response at Follow-up Week 24 (SVR24) by rs12979860 Single Nucleotide Polymorphism (SNP) in the IL28B Gene
    End point description
    Subjects categorized into three genotypes based on SNPs in the IL28B gene were assessed for SVR12 and SVR24, defined as response in which HCV RNA levels below LLOQ or below TD or TND at follow-up Week 12 and Week 24 respectively. For SVR12: analysis was performed by backward imputation method, For SVR24: analysis was performed in Modified ITT population.
    End point type
    Secondary
    End point timeframe
    Post Treatment Weeks 12, 24
    End point values
    		 Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Number of subjects analysed
    82
    42
    Units: Percentage of Subjects
    number (not applicable)
        IL28B Genotype CC (SVR12) (n=22,9)
    95.5
    100
        IL28B Genotype CT (SVR12) (n=40,27)
    75
    33.3
        IL28B Genotype TT (SVR12) (n=20,6)
    80
    0
        IL28B Genotype CC (SVR24) (n=22,9)
    95.5
    88.9
        IL28B Genotype CT (SVR24) (n=40,27)
    72.5
    33.3
        IL28B Genotype TT (SVR24) (n=20,6)
    80
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to last dose plus 7 days (up to Week 49)
    Adverse event reporting additional description
    On-treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Daclatasvir+ PegIFNα-2a + Ribavirin
    Reporting group description
    		 Daclatasvir 60 mg tablets were administered orally once daily for 24 weeks, PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 24 or 48 weeks depending on response and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 24 or 48 weeks depending on response.

    Reporting group title
    Placebo + PegIFNα-2a + Ribavirin
    Reporting group description
    		 Placebo matching daclatasvir tablets was administered orally once daily for 48 weeks. PegIFNalfa-2a 180 µg was administered subcutaneously once in a week for 48 weeks and ribavirin 400 mg (2 tablets for subjects <75 kg) or 600 mg (3 tablets for subjects >=75 kg) was administered orally in the morning and 600 mg (3 tablets) in the evening for 48 weeks.

    Serious adverse events
    		 Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 82 (9.76%)
    2 / 42 (4.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid cancer metastatic
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cluster headache
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Daclatasvir+ PegIFNα-2a + Ribavirin Placebo + PegIFNα-2a + Ribavirin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 82 (97.56%)
    39 / 42 (92.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 82 (34.15%)
    11 / 42 (26.19%)
         occurrences all number
    30
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 82 (24.39%)
    12 / 42 (28.57%)
         occurrences all number
    23
    15
    Neutropenia
         subjects affected / exposed
    12 / 82 (14.63%)
    11 / 42 (26.19%)
         occurrences all number
    14
    14
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    47 / 82 (57.32%)
    25 / 42 (59.52%)
         occurrences all number
    48
    26
    Fatigue
         subjects affected / exposed
    6 / 82 (7.32%)
    7 / 42 (16.67%)
         occurrences all number
    6
    8
    Influenza like illness
         subjects affected / exposed
    23 / 82 (28.05%)
    13 / 42 (30.95%)
         occurrences all number
    25
    15
    Irritability
         subjects affected / exposed
    11 / 82 (13.41%)
    9 / 42 (21.43%)
         occurrences all number
    11
    9
    Pyrexia
         subjects affected / exposed
    13 / 82 (15.85%)
    8 / 42 (19.05%)
         occurrences all number
    13
    10
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 42 (9.52%)
         occurrences all number
    3
    4
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    7 / 82 (8.54%)
    5 / 42 (11.90%)
         occurrences all number
    7
    7
    Constipation
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 42 (7.14%)
         occurrences all number
    2
    3
    Diarrhoea
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 42 (9.52%)
         occurrences all number
    8
    4
    Dry mouth
         subjects affected / exposed
    3 / 82 (3.66%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    Dyspepsia
         subjects affected / exposed
    3 / 82 (3.66%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    Nausea
         subjects affected / exposed
    10 / 82 (12.20%)
    5 / 42 (11.90%)
         occurrences all number
    10
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 82 (12.20%)
    8 / 42 (19.05%)
         occurrences all number
    11
    10
    Dyspnoea
         subjects affected / exposed
    5 / 82 (6.10%)
    8 / 42 (19.05%)
         occurrences all number
    5
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 82 (8.54%)
    2 / 42 (4.76%)
         occurrences all number
    7
    2
    Dry skin
         subjects affected / exposed
    12 / 82 (14.63%)
    7 / 42 (16.67%)
         occurrences all number
    12
    7
    Eczema
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 42 (9.52%)
         occurrences all number
    3
    4
    Erythema
         subjects affected / exposed
    2 / 82 (2.44%)
    5 / 42 (11.90%)
         occurrences all number
    2
    6
    Pruritus
         subjects affected / exposed
    25 / 82 (30.49%)
    13 / 42 (30.95%)
         occurrences all number
    30
    18
    Rash
         subjects affected / exposed
    15 / 82 (18.29%)
    8 / 42 (19.05%)
         occurrences all number
    17
    10
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 42 (9.52%)
         occurrences all number
    3
    4
    Depression
         subjects affected / exposed
    3 / 82 (3.66%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    Insomnia
         subjects affected / exposed
    18 / 82 (21.95%)
    6 / 42 (14.29%)
         occurrences all number
    19
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 82 (10.98%)
    6 / 42 (14.29%)
         occurrences all number
    9
    8
    Back pain
         subjects affected / exposed
    11 / 82 (13.41%)
    6 / 42 (14.29%)
         occurrences all number
    12
    6
    Myalgia
         subjects affected / exposed
    15 / 82 (18.29%)
    11 / 42 (26.19%)
         occurrences all number
    16
    14
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    5 / 82 (6.10%)
    1 / 42 (2.38%)
         occurrences all number
    5
    1
    Decreased appetite
         subjects affected / exposed
    20 / 82 (24.39%)
    5 / 42 (11.90%)
         occurrences all number
    21
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2011
    1) Restricted enrollment to subjects chronically infected with HCV GT-4, rather than HCV GT-1 and GT-4, across all study sites. The population sample size and statistical analysis were adjusted to accommodate this change. 2) Changed primary objective to compare rates of SVR12 for HCV GT-4 infected subjects treated with either DCV or placebo in combination with pegIFNalfa-2a/RBV, not GT-1 subjects. 3) Added OATP1B3, atorvastatin, methotrexate, thryoxine, mitoxantrone, imatinib, irinotecan, lapatinib, sulfasalazine, and topotecan as prohibited or restricted treatments during DCV dosing. 4) Corrected the exceptions for unblinding to include subjects who reach virologic failure, not treatment futility. 5) Updated the sample size determination to reflect the change of enrolling GT-4 subjects, not GT-1 subjects.
    19 Jul 2013
    1) Clarified that that enrollment into a 3-year observational study may be offered to subjects following the completion of the follow-up phase of this study to assess long-term SVR, resistance, and HCV-related complications. 2) Added QTcB >500 msec to the exclusion criteria. 3) Clarified co-administration of prednisone and prednisolone were to be avoided, but used with caution if deemed necessary. 4) Reduced requirement for monitoring of blood pressure when erythropoiesis-stimulating agents (ESA) initiated. 5) Added instructions for missed doses of DCV and RBV. 6) Clarified that the pharmacokinetic (PK) assessments of DCV and RBV would be based on plasma and concentrations and PK assessments of pegIFNalfa-2a would be based on serum concentrations. 7) Table for Grading the Severity of Adult and Pediatric Adverse Events was to be used for grading laboratory abnormalities reported as AEs or SAEs.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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